In this project we investigate the physiological properties of the neural pathways that mediate the effect of light and serotonin (5HT) agonists on the timing of daily and seasonal biological rhythms. The timing of these rhythms is regulated by a circadian clock located in the suprachiasmatic nucleus (SCN). Exposure to a) light and b) serotonergic agonists, resets the timing of the clock and the pattern of behaviors controlled by the clock. The capacity of these two factors to reset the circadian clock is being evaluated in this project. We have found that antidepressant drug treatments alter the phase-resetting effects of light. This behavioral response is accompanied by a decrease in c-fos expression within SCN cells. Second, we have found that phase-resetting by 5HT agonists and benzodiazepines in decreased by chronic antidepressant drug treatment. The sensitivity of the phase-resetting response to light is constant over twenty-four hours, but chronic treatment with the antidepressant drug, clorgyline, differentially alters sensitivity to light at different phases of the twenty-four hour cycle. Thus, more light is required to produce a 50% phase-shift response to morning light than to produce a 50% response to evening light. Our data suggests that lithium fails to alter the sensitivity or responsiveness of the photic entrainment pathway, although lithium was found by other groups to alter visual responses as measured by electrooculographic and neurophysiological techniques. The fact that lithium alters visual responses, but not entrainment responses to light underscores the need to conduct further research on this specific and distinct photic system. We have recently found that clorgyline treatment decreases c-fos expression within SCN cells that receive a projection from the retinohypothalamic tract. The 50% decrease in cells expressing c-fos is consistent with the 50% decrease in the magnitude of the phase-resetting response to light, but not to the smaller decrease in photic sensitivity. This molecular marker will be a useful technique for further evaluating antidepressant drug effects on entrainment to the light-dark cycle. Experiments completed during the past year indicate that chronic treatment with antidepressant drugs alter phase-resetting by the 5HT agonist 8 OH DPAT, and by the benzodiazepine triazolam. DPAT-induced phase-shifts are smaller in clorgyline-treated hamsters than controls suggesting a possible desensitization of 5HT receptors. The decreased phase-shifting response following injections by a 5HT 1A agonist and a benzodiazepine, indicates that chronic antidepressant drugs may diminish the feedback effects of behavior on the circadian clock.